Daily Endocrinology Research Analysis
Analyzed 110 papers and selected 3 impactful papers.
Summary
Proteomics-enabled risk stratification in MASLD markedly improved prediction of major adverse liver outcomes, while a large target-trial emulation suggests GLP-1 receptor agonists add kidney protection on top of SGLT2 inhibitors in type 2 diabetes. A simplified, externally validated diagnostic nomogram for adult hypophosphatasia enables accurate recognition without PLP testing, supporting earlier endocrine bone disease diagnosis.
Research Themes
- Proteomics-driven precision risk prediction in metabolic liver disease
- Additive kidney protection from combined incretin–SGLT2 therapy in T2D
- Point-of-care diagnostic tools for rare endocrine bone disorders
Selected Articles
1. Large-Scale Plasma Proteomics Improves Prediction of Major Adverse Liver Outcomes in Individuals With MASLD.
In a 14,166-participant MASLD cohort, 834 plasma proteins were associated with future cirrhosis/HCC and a 13-protein risk score substantially improved prediction (C-index 0.880; +0.072 over clinical model). The proteomic score correlated with MRI-derived cT1, linking the signature to liver disease activity.
Impact: This large, methodologically rigorous proteomics study advances precision hepatometabolic risk stratification with immediate translational potential for MASLD care pathways.
Clinical Implications: Integrating a validated proteomic risk score could help identify MASLD patients at highest risk for cirrhosis/HCC, prioritize hepatology referrals, and tailor surveillance intensity beyond conventional clinical indices.
Key Findings
- Among 14,166 MASLD participants, 834 proteins were associated with major adverse liver outcomes after multivariable adjustment (FDR<0.01).
- A 13-protein elastic-net–derived risk score improved prediction (C-index 0.880; increment +0.072) and reclassification metrics (NRI/IDI).
- The proteomic risk score correlated with MRI cT1 (β=7.50 per SD), linking molecular risk to liver disease activity.
Methodological Strengths
- Large prospective cohort with long follow-up and comprehensive covariate adjustment
- High-dimensional proteomics with elastic-net selection and cross-validated performance metrics, plus imaging correlation (cT1)
Limitations
- Observational design with potential residual confounding and need for external validation across healthcare systems
- Low absolute event rate (1.1%) may affect transportability and calibration in different populations
Future Directions: Prospective external validation, clinical utility studies (decision-curve analysis, cost-effectiveness), and integration into risk-based surveillance algorithms for MASLD.
AIMS: Cirrhosis and hepatocellular carcinoma are severe major adverse liver outcomes (MALOs) of metabolic dysfunction-associated steatotic liver disease (MASLD), yet the relationship between proteomics and MALOs remains unclear. This study aimed to identify plasma proteomic features associated with MALOs and evaluate the potential of proteomics to enhance the prediction of MALOs risks in individuals with MASLD. MATERIALS AND METHODS: This prospective cohort study included 14 166 participants with MASLD from the UK Biobank. Associations between 2920 plasma proteins and incident MALOs were assessed using multivariable Cox proportional hazards regression models. Proteomic predictors were selected using elastic net-penalised Cox regression with five-fold cross-validation and a protein risk score (ProRS) was derived. Predictive performance was evaluated in validation sets using Harrell's C-index, category-free net reclassification improvement (NRI) and integrated discrimination improvement (IDI). Associations between the ProRS and liver disease activity were further examined using multivariable linear regression with MRI-derived iron-corrected T1 (cT1) values. RESULTS: Over a median follow-up of 13.4 years, 151 participants (1.1%) developed MALOs. We identified 834 proteins (803 positively and 31 inversely) associated with MALOs in multivariable analysis (false discovery rate-adjusted p-value < 0.01), primarily enriched in pathways related to cell adhesion, extracellular region, cytokine activity and cytokine-cytokine receptor interactions. The top five proteins positively associated with increased risks of MALOs were CDHR2, CEACAM1, FCAMR, LTBP2 and GGT1, while TTR, APOM, KITLG, C1orf56 and PROC showed inverse associations. Incorporation of the ProRS derived from 13 elastic net-selected proteins significantly improved the prediction of MALOs, achieving a C-index of 0.880 (95% CI: 0.847, 0.910) with an increment of 0.072 (95% CI: 0.041, 0.102). Furthermore, each standard deviation increase in ProRS was associated with higher cT1 values (β = 7.50; 95% CI: 1.91, 13.10). CONCLUSIONS: This study identified plasma proteins associated with MALOs in individuals with MASLD. Incorporation of a proteomics-derived risk score into the clinical model significantly improved predictive performance and was associated with greater liver disease activity, suggesting the potential to enable more precise risk stratification and personalised management.
2. Kidney outcomes with GLP-1 receptor agonists in people with type 2 diabetes already receiving SGLT2 inhibitors: a target trial emulation study using UK primary care data.
In a UK primary care target-trial emulation of 33,659 treatment initiations on an SGLT2 background, GLP-1 receptor agonists were associated with a 27% lower risk of kidney disease progression versus DPP-4 inhibitors or sulfonylureas (HR 0.73). No excess acute pancreatitis was observed.
Impact: Provides high-quality real-world evidence supporting additive kidney protection with GLP-1 RAs on top of SGLT2 inhibitors, informing treatment sequencing in primary care.
Clinical Implications: Clinicians may consider GLP-1 RA initiation for additional kidney protection in T2D patients already on SGLT2 inhibitors, especially in those at high absolute renal risk, while monitoring for standard safety signals.
Key Findings
- Active-comparator new-user cohort showed lower kidney disease progression with GLP-1 RAs vs DPP-4i/SUs (HR 0.73; 95% CI 0.58–0.92).
- No increased acute pancreatitis signal observed after GLP-1 RA initiation among those without prior pancreatitis history.
- Findings support combination therapy for kidney protection in primary care on top of SGLT2 inhibitors.
Methodological Strengths
- Target trial emulation with active-comparator, new-user design reduces confounding by indication
- Linked primary care, hospital, deprivation, and mortality data with large sample size
Limitations
- Observational nature with residual confounding and potential misclassification in EHR data
- Median follow-up 1.4 years limits assessment of long-term renal endpoints
Future Directions: Prospective randomized evaluation of GLP-1 RA plus SGLT2 vs monotherapy on renal endpoints and assessment of patient subgroups with highest absolute benefit.
BACKGROUND: Type 2 diabetes is the leading cause of kidney failure and is predominantly managed in primary care. Large randomised trials have shown that GLP-1 receptor agonists and SGLT2 inhibitors each slow kidney disease progression, but their combined effect on kidney outcomes remains unclear. We aimed to evaluate the comparative effectiveness of GLP-1 receptor agonists versus DPP-4 inhibitors or sulfonylureas on kidney outcomes in individuals with type 2 diabetes already receiving SGLT2 inhibitor treatment. METHODS: In this observational study, we emulated a pragmatic target trial using an active-comparator, new-user cohort design with UK primary care electronic health record data (Clinical Practice Research Datalink, March 31, 2013-March 31, 2023) with linkage to hospital inpatient, deprivation, and mortality data. We included individuals with type 2 diabetes already receiving SGLT2 inhibitors who newly initiated either GLP-1 receptor agonists or comparator drugs DPP-4 inhibitors or sulfonylureas. We excluded those with estimated glomerular filtration rate (eGFR) of less than 20 mL/min per 1·73 m FINDINGS: We included 33 659 treatment initiations (20 039 GLP-1 receptor agonists and 13 620 DPP-4 inhibitors or sulfonylureas; among 31 650 unique individuals), of whom these initiations occurred among 20 239 (60%) male individuals and 13 420 (40%) female individuals; median age was 60 years (IQR 53-67), and 26 530 (79%) were White, 4492 (13%) south Asian, 1398 (4%) Black, and 1239 (4%) of other ethnicities. Over a median follow-up of 1·4 years (IQR 0·6-3·0), kidney disease progression occurred in 187 (0·9%) of 20 039 individuals who initiated a GLP-1 receptor agonist and 189 (1·4%) of 13 620 who initiated a DPP-4 inhibitor or sulfonylurea. GLP-1 receptor agonist initiation was associated with a lower risk of kidney disease progression compared with DPP-4 inhibitor or sulfonylurea initiation (HR 0·73 [95% CI 0·58-0·92]). GLP-1 receptor agonist initiation was not associated with occurrence of acute pancreatitis (32 [0·2%] of 19 727 individuals with no recorded history of pancreatitis who initiated a GLP-1 receptor agonist INTERPRETATION: These real-world data suggest that the kidney-protective benefits of GLP-1 receptor agonists observed in randomised trials of individuals with type 2 diabetes might also extend to individuals already receiving SGLT2 inhibitors. This finding supports consideration of combination treatment for kidney protection in primary care, particularly in individuals at highest absolute risk. Further prospective data would be valuable to confirm these findings. FUNDING: UK Medical Research Council.
3. Identification of hypophosphatasia in adults with persistent hypophosphatasemia: clinical-genetic characterization and a validated diagnostic tool.
Among 72 genetically confirmed adult HPP cases versus 36 persistent hypophosphatasemia controls, a four-variable model (ALP, height Z-score, family history, chronic musculoskeletal pain) achieved AUC 0.918 and externally validated at 0.833. Cutoffs for ALP (28.2 U/L) and PLP (114.9 nmol/L) were defined.
Impact: Delivers an externally validated, low-resource diagnostic tool to recognize adult hypophosphatasia without PLP testing, addressing a key gap in endocrine bone disease diagnostics.
Clinical Implications: Use of a four-variable nomogram can prompt earlier HPP recognition, genetic testing, and tailored management (e.g., asfotase alfa consideration, avoidance of antiresorptives) in adults with low ALP.
Key Findings
- Model 1 (ALP + height Z-score + family history + chronic musculoskeletal pain) achieved AUC 0.918, comparable to ALP+PLP model (AUC 0.896).
- External validation (n=40; 28 HPP) showed AUC 0.833, supporting generalizability.
- Optimal ALP and PLP cutoffs identified (28.2 U/L and 114.9 nmol/L); ALPL crown-domain variants associated with lower ALP/higher PLP.
Methodological Strengths
- Genetically confirmed cases and prespecified control group with persistent hypophosphatasemia
- Model development with cross-validation, decision-curve analysis, and external validation
Limitations
- Single-country cohort with moderate sample size; potential selection bias
- Generalizability to non-Asian populations and community settings requires further study
Future Directions: Prospective multicenter validation, calibration in diverse populations, and implementation studies assessing diagnostic yield and impact on management decisions.
UNLABELLED: This study systematically analyzed 72 adults with genetically confirmed hypophosphatasia and compared them with 36 individuals with persistent hypophosphatasemia but negative ALPL variants. Using four routinely available indicators, a simplified diagnostic tool was developed and externally validated to facilitate the early identification of adult hypophosphatasia in clinical practice. PURPOSE: Hypophosphatasia (HPP), an underdiagnosed inborn error of disorder caused by ALPL mutations, poses diagnostic challenges in adults due to phenotypic heterogeneity. This study aimed to establish a large adult HPP cohort in China and develop a practical diagnostic tool using routine clinical parameters. METHODS: Clinical and genetic characteristics were systematically analyzed in 72 genetically confirmed adult HPP patients and 36 individuals with persistent hypophosphatasemia and negative ALPL genetic testing. Two models were developed to predict HPP: Model 0 (alkaline phosphatase (ALP)+pyridoxal-5'-phosphate (PLP)) and Model 1 (ALP+height Z-score+family history+chronic musculoskeletal pain). Model performance was evaluated by tenfold cross-validation, decision curve analysis (DCA) and external validation (n = 40, including 28 HPP). RESULTS: HPP patients exhibited lower ALP (27.0 (21.8, 33.3) U/L vs. 36.00 (32.0, 38.0) U/L; P < 0.001), elevated PLP (214.3 (121.3, 457.7) nmol/L vs. 42.6 (31.9, 63.5) nmol/L; P < 0.001), growth impairment, and higher prevalence of chronic musculoskeletal pain and family history. Optimal ALP and PLP cutoffs were 28.2 U/L and 114.9 nmol/L, respectively. Compound heterozygotes and crown domain variants in ALPL gene showed lower ALP and higher PLP levels. Model 1 performed comparably to Model 0 (AUC 0.918 vs. 0.896; P = 0.513), remained robust in the age-stratified sensitivity analysis (<50 years), and achieved an AUC of 0.833 in external validation. A nomogram based on Model 1 was constructed. CONCLUSION: This study provides the largest clinical-genetic characterization of adult HPP in China and proposes a simple four-variable nomogram that enables accurate recognition of HPP without PLP testing, facilitating earlier diagnosis in routine practice.